Hypothesis that systemic and cerebral vascular for the past five years, our group has been testing the disease (even at a subclinical level) modulates the onset of the cognitive syndrome of Alzheimer's disease (AD). We have found that there is an important, but complex, relationship between AD pathology and vascular disease. We have reported that A? deposition is linked to brain structure, markers of cholesterol transport and inflammation. Taken in combination, hippocampal atrophy, white matter lesions, and the extent of A? deposition provided powerful prediction of dementia after two years of follow-up. However, although half of cognitively normal subjects age 85+ were found to have A? deposition, two-thirds of these A?-positive subjects showed no clinical progression over two years. Conversely, one-third of the cognitively normal subjects who progressed to an AD syndrome over two years were A?-negative. These new findings indicate that vascular disease may act as: 1) as a moderating factor that alters brain compensation for AD pathology; 2) as a contributor to AD pathology; or 3) both. The implications of these are critically different and impact our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. The goal of this PPG is to gain further insight into the pre- symptomatic (or subclinical) dynamic processes of the two most common pathologies in old age, vascular disease and AD, in relationship to cognition. In order to longitudinally examine this dynamic process, we have assembled two cohorts: 1) the GEMS cohort of very elderly individuals (~90 yrs) who have been studied by us for 15 years and where the incidence of cognitive syndromes is very high and 2) the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort that is younger (65-75 yrs) and where the expected incidence of cognitive syndromes is much lower. The value of extending our observation of the GEMS cohort through this late stage of frequent clinical change and coupling this to a postmortem study is clear. The importance of the Heart SCORE cohort is that it allows us to see significant changes at the subclinical level (i.e., cognitive decline without reaching the MCI/dementia state). If we observe an association between vascular disease, AD pathology, and cognitive decline in the Heart SCORE cohort, this will strongly support the hypotheses generated from the GEMS cohort. This design allows us to gather in-depth information on the association between vascular disease, AD pathology and cognition within a 5-year period that would otherwise take more than a decade to accumulate. These studies in the GEMS cohort (Project-1) and the Heart SCORE cohort (Project-2) are enriched by coupling them to the detailed neuropathological evaluations performed in Project-3 and the pharmacokinetic study of the newly applied tau positron emission tomography (PET) technology (Project-4) that aims to simultaneously add missing components to the characterization of tau-PET and improve the accuracy and value of the tau-PET data acquired in this PPG - and by the field in general.